Substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and-1-oxoisoindolines and method of reducing TNFalpha levels

ABSTRACT

Substituted 2-(2,6-dioxopiperidin-3-yl)phthalimides and 1-oxo-2-(2,6-dioxopiperidin-3-yl)isoindolines reduce the levels of TNFα in a mammal. A typical embodiment is 1-oxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4,5,6,7-tetrafluoroisoindoline.

[0001] The present invention relates to substituted2-(2,6-dioxopiperidin-3-yl)-phthalimides and substituted2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines, the method of reducinglevels of tumor necrosis factor α and treating inflammatory andautoimmune diseases in a mammal through the administration thereof, andto pharmaceutical compositions of such derivatives.

BACKGROUND OF THE INVENTION

[0002] Tumor necrosis factor α, or TNFα, is a cytokine which is releasedprimarily by mononuclear phagocytes in response to a numberimmunostimulators. When administered to animals or humans, it causesinflammation, fever, cardiovascular effects, hemorrhage, coagulation,and acute phase responses similar to those seen during acute infectionsand shock states. Excessive or unregulated TNFα production thus has beenimplicated in a number of disease conditions. These include endotoxemiaand/or toxic shock syndrome {Tracey et al., Nature 330, 662-664 (1987)and Hinshaw et al., Circ Shock 30, 279-292 (1990),; cachexia {Dezube etal., Lancet. 335 (8690), 662 (1990), and Adult Respiratory DistressSyndrome where TNFα concentration in excess of 12,000 pg/mL have beendetected in pulmonary aspirates from ARDS patients {Millar et al.,Lancet 2(8665). 712-714 (1989)}. Systemic infusion of recombinant TNFαalso resulted in changes typically seen in ARDS {Ferrai-Baliviera etal., Arch. Surg. 124(12), 1400-1405 (1989)}.

[0003] TNFα appears to be involved in bone resorption diseases,including arthritis. When activated, leukocytes will producebone-resorption, an activity to which the data suggest TNFα contributes.{Bertolini et al., Nature 319, 516-518 (1986) and Johnson et al.,Endocrinology 124(3), 1424-1427 (1989).} TNFα also has been shown tostimulate bone resorption and inhibit bone formation in vitro and invivo through stimulation of osteoclast formation and activation combinedwith inhibition of osteoblast function. Although TNFα may be involved inmany bone resorption diseases, including arthritis, the most compellinglink with disease is the association between production of TNFα by tumoror host tissues and malignancy associated hypercalcemia {Calci. TissueInt. (US) 46(Suppl.), S3-10 (1990)}. In Graft versus Host Reaction,increased serum TNFα levels have been associated with major complicationfollowing acute allogenic bone marrow transplants {Holler et al., Blood,75(4), 1011-1016 (1990)}.

[0004] Cerebral malaria is a lethal hyperacute neurological syndromeassociated with high blood levels of TNFα and the most severecomplication occurring in malaria patients. Levels of serum TNFαcorrelated directly with the severity of disease and the prognosis inpatients with acute malaria attacks {Grau et al., N. Engl. J. Med.320(24), 1586-1591 (1989)}.

[0005] Macrophage-induced angiogenesis is known to be mediated by TNFα.Leibovich et al. {Nature, 329, 630-632 (1987)} showed TNFα induces invivo capillary blood vessel formation in the rat cornea and thedeveloping chick chorioallantoic membranes at very low doses and suggestTNFα is a candidate for inducing angiogenesis in inflammation, woundrepair, and tumor growth. TNFα production also has been associated withcancerous conditions, particularly induced tumors {Ching et al., Brit.J. Cancer, (1955) 72, 339-343, and Koch, Progress in MedicinalChemistry, 22 166-242 (1985)}.

[0006] TNFα also plays a role in the area of chronic pulmonaryinflammatory diseases. The deposition of silica particles leads tosilicosis, a disease of progressive respiratory failure caused by afibrotic reaction. Antibody to TNFα completely blocked thesilica-induced lung fibrosis in mice {Pignet et al., Nature, 344:245-247(1990)}. High levels of TNFα production (in the serum and in isolatedmacrophages) have been demonstrated in animal models of silica andasbestos induced fibrosis {Bissonnette et al., Inflammation 13(3),329-339 (1989)}. Alveolar macrophages from pulmonary sarcoidosispatients have also been found to spontaneously release massivequantities of TNFα as compared with macrophages from normal donors{Baughman et al., J. Lab. Clin. Med. 115(1), 36-42 (1990)}.

[0007] TNFα is also implicated in the inflammatory response whichfollows reperfusion, called reperfusion injury, and is a major cause oftissue damage after loss of blood flow {Vedder et al., PNAS 87,2643-2646 (1990)). TNFα also alters the properties of endothelial cellsand has various pro-coagulant activities, such as producing an increasein tissue factor pro-coagulant activity and suppression of theanticoagulant protein C pathway as well as down-regulating theexpression of thrombomodulin {Sherry et al., J. Cell Biol. 107,1269-1277 (1988)}. TNFα has pro-inflammatory activities which togetherwith its early production (during the initial stage of an inflammatoryevent) make it a likely mediator of tissue injury in several importantdisorders including but not limited to, myocardial infarction, strokeand circulatory shock. Of specific importance may be TNFα-inducedexpression of adhesion molecules, such as intercellular adhesionmolecule (ICAM) or endothelial leukocyte adhesion molecule (ELAM) onendothelial cells {Munro et al., Am. J. Path. 135(1), 121-1332 (1989)}.

[0008] TNFα blockage with monoclonal anti-TNFα antibodies has been shownto be beneficial in rheumatoid arthritis {Elliot et al., Int. J.Pharmac. 1995 17(2), 141-145} and Crohn's disease {von Dullemen et al.,Gastroenterology, 1995 109(1), 129-135}

[0009] Moreover, it now is known that TNFα is a potent activator ofretrovirus replication including activation of HIV-1. {Duh et al., Proc.Nat. Acad. Sci. 86, 5974-5978 (1989); Poll et al., Proc. Nat. Acad. Sci.87, 782-785 (1990); Monto et al., Blood 79, 2670 (1990); Clouse et al.,J. Immunol. 142, 431-438 (1989); Poll et al., AIDS Res. Hum. Retrovirus,191-197 (1992)}. AIDS results from the infection of T lymphocytes withHuman Immunodeficiency Virus (HIV). At least three types or strains ofHIV have been identified. i.e., HIV-1, HIV-2 and HIV-3. As a consequenceof HIV infection. T-cell mediated immunity is impaired and infectedindividuals manifest severe opportunistic infections and/or unusualneoplasms. HIV entry into the T lymphocyte requires T lymphocyteactivation. Other viruses, such as HIV-1. HIV-2 infect T lymphocytesafter T cell activation and such virus protein expression and/orreplication is mediated or maintained by such T cell activation. Once anactivated T lymphocyte is infected with HIV, the T lymphocyte mustcontinue to be maintained in an activated state to permit HIV geneexpression and/or HIV replication. Cytokines, specifically TNFα, areimplicated in activated T-cell mediated HIV protein expression and/orvirus replication by playing a role in maintaining T lymphocyteactivation. Therefore, interference with cytokine activity such as byprevention or inhibition of cytokine production, notably TNFα, in anHIV-infected individual assists in limiting the maintenance of Tlymphocyte caused by HIV infection.

[0010] Monocytes, macrophages, and related cells, such as kupffer andglial cells, also have been implicated in maintenance of the HIVinfection. These cells, like T cells, are targets for viral replicationand the level of viral replication is dependent upon the activationstate of the cells. {Rosenberg et al., The Immunopathogenesis of HIVInfection, Advances in Immunology, 57 (1989)}. Cytokines, such as TNFα,have been shown to activate HIV replication in monocytes and/ormacrophages {Poli et al., Proc. Natl. Acad. Sci., 87, 782-784 (1990)},therefore, prevention or inhibition of cytokine production or activityaids in limiting HIV progression for T cells. Additional studies haveidentified TNFα as a common factor in the activation of HIV in vitro andhas provided a clear mechanism of action via a nuclear regulatoryprotein found in the cytoplasm of cells (Osborn, et al., PNAS 862336-2340). This evidence suggests that a reduction of TNFα synthesismay have an antiviral effect in HIV infections, by reducing thetranscription and thus virus production.

[0011] AIDS viral replication of latent HIV in T cell and macrophagelines can be induced by TNFα {Folks et al., PNAS 86, 2365-2368 (1989)}.A molecular mechanism for the virus inducing activity is suggested byTNFα's ability to activate a gene regulatory protein (NFκB) found in thecytoplasm of cells, which promotes HIV replication through binding to aviral regulatory gene sequence (LTR) {Osborn et al., PNAS 86, 2336-2340(1989)}. TNFα in AIDS associated cachexia is suggested by elevated serumTNFα and high levels of spontaneous TNFα production in peripheral bloodmonocytes from patients {Wright et al., J. Immunol. 141(1), 99-104(1988)}. TNFα has been implicated in various roles with other viralinfections, such as the cytomegalia virus (CMV), influenza virus,adenovirus, and the herpes family of viruses for similar reasons asthose noted.

[0012] The nuclear factor κB (NFκB) is a pleiotropic transcriptionalactivator (Lenardo, et al, Cell 1989, 58, 227-29). NFκB has beenimplicated as a transcriptional activator in a variety of disease andinflammatory states and is thought to regulate cytokine levels includingbut not limited to TNFα and also to be an activator of HIV transcription(Dbaibo, et al., J. Biol. Chem. 1993, 17762-66; Duh et al., Proc. Natl.Acad. Sci. 1989, 86, 5974-78; Bachelerie at al., Nature 1991, 350,709-12; Boswas et aL, J. Acquired Immune Deficiency Syndrome 1993, 6,778-786; Suzuki et al., Biochem. And Biophys. Res. Comm. 1993, 193,277-83; Suzuki et al., Biochem. And Biophys. Res Comm. 1992, 189,1709-15; Suzuki et al., Biochem. Mol. Bio. Int. 1993, 31(4), 693-700;Shakhov et al., Proc. Natl. Acad. Sci. USA 1990, 171, 35-47; and Staalet al., Proc. Natl. Acad. Sci. USA 1990, 87, 9943-47). Thus, inhibitionof NFκB binding can regulate transcription of cytokine gene(s) andthrough this modulation and other mechanisms be useful in the inhibitionof a multitude of disease states. The compounds described herein caninhibit the action of NFκB in the nucleus and thus are useful in thetreatment of a variety of diseases including but not limited torheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, otherarthritic conditions, septic shock, septis, endotoxic shock, graftversus host disease, wasting, Crohn's disease, inflammatory boweldisease, ulcerative colitis, multiple sclerosis, systemic lupuserythrematosis, ENL in leprosy, HIV, AIDS, and opportunistic infectionsin AIDS. TNFα and NFκB levels are influenced by a reciprocal feedbackloop. As noted above, the compounds of the present invention affect thelevels of both TNFα and NFκB.

[0013] Many cellular functions are mediated by levels of adenosine3′,5′-cyclic monophosphate (cAMP). Such cellular functions cancontribute to inflammatory conditions and diseases including asthma,inflammation, and other conditions (Lowe and Cheng, Drugs of the Future,17(9), 799-807, 1992). It has been shown that the elevation of cAMP ininflammatory leukocytes inhibits their activation and the subsequentrelease of inflammatory mediators, including TNFα and NFκB. Increasedlevels of cAMP also leads to the relaxation of airway smooth muscle.

[0014] Decreasing TNFα levels and/or increasing cAMP levels thusconstitutes a valuable therapeutic strategy for the treatment of manyinflammatory, infectious, immunological or malignant diseases. Theseinclude but are not restricted to septic shock, sepsis, endotoxic shock,hemodynamic shock and sepsis syndrome, post ischemic reperfusion injury,malaria, mycobacterial infection, meningitis, psoriasis, congestiveheart failure, fibrotic disease, cachexia, graft rejection, cancer,autoimmune disease, opportunistic infections in AIDS, rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, other arthriticconditions, Crohn's disease, ulcerative colitis, multiple sclerosis,systemic lupus erythrematosis. ENL in leprosy, radiation damage, andhyperoxic alveolar injury. Prior efforts directed to the suppression ofthe effects of TNFα have ranged from the utilization of steroids such asdexamethasone and prednisolone to the use of both polyclonal andmonoclonal antibodies {Beutler et al., Science 234, 470-474 (1985); WO92/11383}.

DETAILED DESCRIPTION

[0015] The present invention is based on the discovery that certainclasses of non-polypeptide compounds more fully described hereindecrease the levels of TNFα.

[0016] In particular, the invention pertains to compounds of theformula:

[0017] in which:

[0018] one of X and Y is C═O and the other of X and Y is C═O or CH₂;

[0019] (i) each of R¹, R², R³, and R⁴, independently of the others, ishalo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or(ii) one of R¹, R², R³, and R⁴ is

[0020] —NHR and the remaining of R¹, R², R³, and R⁴ are hydrogen;

[0021] R⁵ is hydrogen or alkyl of 1 to 8 carbon atoms;

[0022] R⁶ is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro, orfluoro;

[0023] R⁷ is m-phenylene or p-phenylene or —(C_(n)H_(2n))— in which nhas a value of 0 to 4;

[0024] each of R⁸ and R⁹ taken independently of the other is hydrogen oralkyl of 1 to 8 carbon atoms, or R⁸ and R⁹ taken together aretetramethylene, pentamethylene, hexamethylene, or —CH₂CH₂XCH₂CH₂— inwhich X is —O—, —S— or —NH—;

[0025] R¹⁰ is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl; and

[0026] (b) the acid addition salts of said compounds which contain anitrogen atom capable of being protonated.

[0027] A first preferred group of compounds are those of Formula I inwhich at least one of of R¹, R², R³, R⁴, and R⁶ is other than hydrogen.Among these, a preferred group are those compounds in which each of R¹,R², R³, and R⁴, independently of the others, is halo, alkyl of 1 to 4carbon atoms, or alkoxy of 1 to 4 carbon atoms; R⁶ is hydrogen, methyl,ethyl, or propyl; ; each of R⁸ and R⁹ taken independently of the otheris hydrogen or methyl; and R¹⁰ is hydrogen. Of these compounds, apreferred subgroup are those compounds in which R⁷ is m-phenylene orp-phenylene while a second preferred subgroup are those compounds inwhich R⁷—(C_(n)H_(2n))— in which n has a value of 0 to 4.

[0028] A further preferred group of compounds are those of Formula I inwhich one of R¹, R², R³, and R⁴ is —NH₂ and the remaining of R¹, R², R³,and R⁴ are hydrogen; R⁶ is hydrogen, methyl, ethyl, or propyl; each ofR⁸ and R⁹ taken independently of the other is hydrogen or methyl; andR¹⁰ is hydrogen. Of these compounds, a first preferred subgroup arethose compounds in which R⁷ is m-phenylene or p-phenylene while a secondpreferred subgroup are those compounds in which R⁷—(C_(n)H_(2n))— inwhich n has a value of 0 to 4.

[0029] The term alkyl denotes a univalent saturated branched or straighthydrocarbon chain containing from 1 to 8 carbon atoms. Representative ofsuch alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, and tert-butyl. Alkoxy refers to an alkyl group bound to theremainder of the molecule through an ethereal oxygen atom.Representative of such alkoxy groups are methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. PreferablyR¹, R², R³, and R⁴ are chloro, fluoro, methyl or methoxy.

[0030] The compounds of Formula I are used, under the supervision ofqualified professionals, to inhibit the undesirable effects of TNFα. Thecompounds can be administered orally, rectally, or parenterally, aloneor in combination with other therapeutic agents including antibiotics,steroids, etc., to a mammal in need of treatment.

[0031] The compounds of the present invention also can be used topicallyin the treatment or prophylaxis of topical disease states mediated orexacerbated by excessive TNFα production, respectively, such as viralinfections, such as those caused by the herpes viruses, or viralconjunctivitis, psoriasis, atopic dermatitis, etc.

[0032] The compounds also can be used in the veterinary treatment ofmammals other than humans in need of prevention or inhibition of TNFαproduction. TNFα mediated diseases for treatment, therapeutically orprophylactically, in animals include disease states such as those notedabove, but in particular viral infections. Examples include felineimmunodeficiency virus, equine infectious anaemia virus, caprinearthritis virus, visna virus, and maedi virus, as well as otherlentiviruses.

[0033] The compounds can be prepared through an initial reaction offormaldehyde with an intermediate of the formula:

[0034] in which X and Y are as defined above;

[0035] each of R₁, R₂, R₃, and R₄, independently of the others, is halo,alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii)one of R₁, R₂, R₃, and R₄ is nitro or protected amino and the remainingof R₁, R₂, R₃, and R₄ are hydrogen; and

[0036] R₆ is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro, orfluoro.

[0037] The resulting N-hydroxymethyl intermediate of Formula II then iscoupled with a carboxylic acid derivative of Formula IV using methodswhich are known in general:

[0038] in which Hal is a reactive halogen such as chloro, bromo, oriodo.

[0039] Protecting groups utilized herein denote groups which generallyare not found in the final therapeutic compounds but which areintentionally introduced at some stage of the synthesis in order toprotect groups which otherwise might be altered in the course ofchemical manipulations. Such protecting groups are removed at a laterstage of the synthesis and compounds bearing such protecting groups thusare of importance primarily as chemical intermediates (although somederivatives also exhibit biological activity). Accordingly the precisestructure of the protecting group is not critical. Numerous reactionsfor the formation and removal of such protecting groups are described ina number of standard works including, for example, “Protective Groups inOrganic Chemistry”, Plenum Press, London and New York, 1973; Greene, Th.W. “Protective Groups in Organic Synthesis”, Wiley, New York, 1981; “ThePeptides”, Vol. I, Schröder and Lubke, Academic Press, London and NewYork, 1965; “Methoden der organischen Chemie”, Houben-Weyl, 4th Edition,Vol.15/I, Georg Thieme Verlag, Stuttgart 1974, the disclosures of whichare incorporated herein by reference.

[0040] An amino group can be protected as an amide utilizing an acylgroup which is selectively removable under mild conditions, especiallybenzyloxycarbonyl, formyl, or a lower alkanoyl group which is branchedin 1- or α position to the carbonyl group, particularly tertiaryalkanoyl such as pivaloyl, a lower alkanoyl group which is substitutedin the position cc to the carbonyl group, as for exampletrifluoroacetyl.

[0041] Coupling agents include such reagents as dicyclohexylcarbodimideand N,N′-carbonyldiimidazole.

[0042] Following coupling, compounds of Formula V can be aminated in aconvention manner, as for example with an amine in the presence ofsodium iodide.

[0043] Alternatively, a compound of Formula III is allowed to react witha protected aminocarboxylic acid of Formula IVA:

[0044] in which Z is a protected amino group.

[0045] Following this coupling, the amino protecting group Z is removed.

[0046] In the foregoing reactions when one of R₁, R₂, R₃, and R₄ isnitro, it can be converted to an amino group by catalytic hydrogenation.Alternatively, if one of R₁, R₂, R₃, and R₄ is protected amino, theprotecting group can be cleaved to yield the corresponding compound inwhich one of R₁, R₂, R₃, and R₄ is amino.

[0047] In addition to serving as intermediates, certain other compoundof Formula IIA are themselves biologically active in reducing levels oftumor necrosis factor a in a mammal. These compounds are those of theformula:

[0048] in which:

[0049] one of X and Y is C═O and the other of X and Y is C═O or CH₂;

[0050] (i) each of R¹, R², R³, and R⁴, independently of the others, ishalo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or(ii) one of R¹, R², R³, and R⁴ is

[0051] NHR⁵ and the remaining of R¹, R², R³, and R⁴ are hydrogen;

[0052] R⁵ is hydrogen, alkyl of 1 to 8 carbon atoms, orCO—R⁷—CH(R¹⁰)NR⁸R⁹ in which each of R⁷, R⁸, R⁹, and R¹⁰ is as hereindefined: and

[0053] R⁶ is alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro.

[0054] Certain of the intermediates of Formula IIA are described incopending applications Ser. Nos. 08/690,258, and 08/701,494, thedisclosures of which are incorporated herein by reference. In addition,an alkyl o-bromomethylbenzoate which is appropriately substituted withR¹, R ², R³, and R⁴ substituents is allowed to react with anα-R⁶-substituted α-aminoglutarimide salt in the presence of an acidacceptor such as triethyl amine to yield compounds in which one of X andY is C═O and the other is CH₂.

[0055] Compounds of Formula IIA in which X and Y are both C═O also canbe prepared by allowing a phthalic an hydride which is appropriatelysubstituted with R¹, R², R³, and R⁴ to react with an α-R⁶-substitutedα-aminoglutarimide salt in the presence of acetic acid and sodiumacetate.

[0056] The α-R⁶-substituted α-aminoglutarimide salt utilized in theforegoing reactions can be obtained by cyclizing an α-R⁶-substitutedglutamine in which the amino group is protected. The cyclization can beconducted for example with N,N′-carbonyldiimidazole in the presence ofan acid acceptor such as dimethylaminopyridine. Upon completion of thereaction, the protecting group can be removed in an appropriate fashion.Solely by way of example, if the protecting group is theN-benzyloxycarbonyl group, it can be removed by catalytic hydrogenation.

[0057] The α-R⁶-substituted glutamines in turn can be prepared bytreating an α-R⁶-substituted glutamic acid anhydride, in which the aminogroup is protected, with ammonia. Finally, the α-R⁶-substituted glutamicacid anhydride can be obtained from the corresponding α-R⁶-substitutedglutamic acid with acetic anhydride.

[0058] The compounds of Formulas I and IIB possess a center of chiralityand can exist as optical isomers. Both the racemates of these isomersand the individual isomers themselves, as well as diastereomers whenthere are two chiral centers, are within the scope of the presentinvention. The racemates can be used as such or can be separated intotheir individual isomers mechanically as by chromatography using achiral absorbant. Alternatively, the individual isomers can be preparedin chiral form or separated chemically from a mixture by forming saltswith a chiral acid, such as the individual enantiomers of10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid,methoxyacetic acid, tartaric acid, diacetyltartaric acid, malic acid,pyrrolidone-5-carboxylic acid, and the like, and then freeing one orboth of the resolved bases, optionally repeating the process, so asobtain either or both substantially free of the other; i.e., in a formhaving an optical purity of >95%.

[0059] The present invention also pertains to the physiologicallyacceptable non-toxic acid addition salts of the compounds of Formulas Iand IIB. Such salts include those derived from organic and inorganicacids such as, without limitation, hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid, methanesulphonic acid, acetic acid,tartaric acid, lactic acid, succinic acid, citric acid, malic acid,maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid,embonic acid, enanthic acid, and the like.

[0060] Oral dosage forms include tablets, capsules, dragees, and similarshaped, compressed pharmaceutical forms containing from 1 to 100 mg ofdrug per unit dosage. Isotonic saline solutions containing from 20 to100 mg/mL can be used for parenteral administration which includesintramuscular, intrathecal, intravenous and intra-arterial routes ofadministration. Rectal administration can be effected through the use ofsuppositories formulated from conventional carriers such as cocoabutter.

[0061] Pharmaceutical compositions thus comprise one or more compoundsof Formulas I IIB associated with at least one pharmaceuticallyacceptable carrier, diluent or excipient. In preparing suchcompositions, the active ingredients are usually mixed with or dilutedby an excipient or enclosed within such a carrier which can be in theform of a capsule or sachet. When the excipient serves as a diluent, itmay be a solid, semi-solid, or liquid material which acts as a vehicle,carrier, or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, elixirs, suspensions,emulsions, solutions, syrups, soft and hard gelatin capsules,suppositories, sterile injectable solutions and sterile packagedpowders. Examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starch, gum acacia, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidinone, cellulose, water,syrup, and methyl cellulose, the formulations can additionally includelubricating agents such as talc, magnesium stearate and mineral oil,wetting agents, emulsifying and suspending agents, preserving agentssuch as methyl- and propylhydroxybenzoates, sweetening agents orflavoring agents.

[0062] The compositions preferably are formulated in unit dosage form,meaning physically discrete units suitable as a unitary dosage, or apredetermined fraction of a unitary dose to be administered in a singleor multiple dosage regimen to human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect in association with a suitablepharmaceutical excipient. The compositions can be formulated so as toprovide an immediate, sustained or delayed release of active ingredientafter administration to the patient by employing procedures well knownin the art.

[0063] Oral dosage forms include tablets, capsules, dragees, and similarshaped, compressed pharmaceutical forms containing from 1 to 100 mg ofdrug per unit dosage. Isotonic saline solutions containing from 20 to100 mg/mL can be used for parenteral administration which includesintramuscular, intrathecal, intravenous and intra-arterial routes ofadministration. Rectal administration can be effected through the use ofsuppositories formulated from conventional carriers such as cocoabutter.

[0064] Pharmaceutical compositions thus comprise one or more compoundsof Formula I associated with at least one pharmaceutically acceptablecarrier, diluent or excipient. In preparing such compositions, theactive ingredients are usually mixed with or diluted by an excipient orenclosed within such a carrier which can be in the form of a capsule orsachet. When the excipient serves as a diluent, it may be a solid,semi-solid, or liquid material which acts as a vehicle, carrier, ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, elixirs, suspensions, emulsions,solutions, syrups, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders. Examples ofsuitable excipients include lactose, dextrose, sucrose, sorbitol,mannitol, starch, gum acacia, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidinone, cellulose, water, syrup, and methylcellulose, the formulations can additionally include lubricating agentssuch as talc, magnesium stearate and mineral oil, wetting agents,emulsifying and suspending agents, preserving agents such as methyl- andpropylhydroxybenzoates, sweetening agents or flavoring agents.

[0065] The compositions preferably are formulated in unit dosage form,meaning physically discrete units suitable as a unitary dosage, or apredetermined fraction of a unitary dose to be administered in a singleor multiple dosage regimen to human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect in association with a suitablepharmaceutical excipient. The compositions can be formulated so as toprovide an immediate, sustained or delayed release of active ingredientafter administration to the patient by employing procedures well knownin the art.

[0066] The following examples will serve to further typify the nature ofthis invention but should not be construed as a limitation in the scopethereof which scope is defined solely by the appended claims.

EXAMPLE 1 N-Benzyloxycarbonyl-α-methyl-glutamic Acid

[0067] To a stirred solution of α-methyl-D,L-glutamic acid (10 g, 62mmol) in 2 N sodium hydroxide (62 mL) at 0-5° C. was added benzylchloroformate (12.7 g, 74.4 mmol) over 30 min. After the addition wascomplete the reaction mixture was stirred at room temperature for 3hours. During this time the pH was maintained at II by addition of 2Nsodium hydroxide (33 mL). The reaction mixture was then extracted withether (60 mL). The aqueous layer was cooled in an ice bath and thenacidified with 4N hydrochloric acid (34 mL) to pH=1. The resultingmixture was extracted with ethyl acetate (3×100 mL). The combined ethylacetate extracts were washed with brine (60 mL) and dried (MgSO₄). Thesolvent was removed in vacuo to give 15.2 g (83%) ofN-benzyloxycarbonyl-α-methylglutamic acid as an oil: ¹H NMR (CDCl₃) δ8.73(m, 5H), 5.77(b, 1H), 5.09(s, 2H), 2.45-2.27(m, 4H), 2.0(s, 3H).

[0068] In a similar fashion from α-ethyl-D,L-glutamic acid andα-propyl-D,L-glutamic acid, there is obtainedN-benzyloxycarbonyl-α-ethylglutamic acid andN-benzyloxycarbonyl-α-propylglutamic acid, respectively.

EXAMPLE 2 N-Benzyloxycarbonyl-α-methyl-glutamic Anhydride

[0069] A stirred mixture of N-benzyloxycarbonyl-α-methyl-glutamic acid(15 g, 51 mmol) and acetic anhydride (65 mL) was heated at reflux undernitrogen for 30 min. The reaction mixture was cooled to room temperatureand then concentrated in vacuo to affordN-benzylcarbonyl-α-methylglutamic anhydride as an oil (15.7 g) which canbe used in next reaction without further purification: ¹H NMR (CDCl₃) δ7.44-7.26 (m, 5H), 5.32-5.30 (m, 2H), 5.11 (s, 1H), 2.69-2.61 (m, 2H),2.40-2.30 (m, 2H), 1.68 (s, 3H).

[0070] In a similar fashion from N-benzyloxycarbonyl-α-ethylglutamicacid and N-benzyloxycarbonyl-α-propylglutamic acid, there is obtainedN-benzylcarbonyl-α-ethylglutamic anhydride andN-benzylcarbonyl-α-propylglutamic anhydride, respectively.

EXAMPLE 3 N-Benzyloxycarbonyl-α-methylisoglutamine

[0071] A stirred solution of N-benzylcarbonyl-α-methylglutamic anhydride(14.2 g, 51.5 mmol) in methylene chloride (100 mL) was cooled in an icebath. Gaseous ammonia was bubbled into the cooled solution for 2 hours.The reaction mixture was stirred at room temperature for 17 hours andthen extracted with water (2×50 mL). The combined aqueous extracts werecooled in an ice bath and acidified with 4N hydrochloric acid (32 mL) topH 1. The resulting mixture was extracted with ethyl acetate (3×80 mL).The combined ethyl acetate extracts were washed with brine (60 mL) andthen dried (MgSO₄). The solvent was removed in vacuo to give 11.5 g ofN-benzyloxycarbonyl-α-amino-α-methylisoglutamine: ¹H NMR (CDCl₃/DMSO) δ7.35 (m, 5H), 7.01 (s, 1H), 6.87 (s, 1H), 6.29 (s, 1H), 5.04 (s, 2H),2.24-1.88 (m, 4H), 1.53 (s, 3H).

[0072] In a similar fashion from N-benzylcarbonyl-α-ethylglutamicanhydride and N-benzylcarbonyl-a:-propylglutamic anhydride there isobtained N-benzyloxycarbonyl-α-amino-α-ethylisoglutamine andN-benzyloxycarbonyl-α-amino-α-propyl isoglutamine, respectively.

EXAMPLE 4 N-Benzyloxycarbonyl-α-amino-α-methylglutarimide

[0073] A stirred mixture of N-benzyloxycarbonyl-α-methylisoglutamine(4.60 g, 15.6 mmol), 1,1′-carbonyldiimidazole (2.80 g, 17.1 mmol), and4-dimethylaminopyridine (0.05 g) in tetrahydrofuran (50 mL) was heatedto reflux under nitrogen for 17 hours. The reaction mixture was thenconcentrated in vacuo to an oil. The oil was slurried in water (50 mL)for 1 hour. The resulting suspension was filtered and the solid washedwith water and air dried to afford 3.8 g of the crude product as a whitesolid. The crude product was purified by flash chromatography (methylenechloride:ethyl acetate 8:2) to afford 2.3 a (50%) ofN-benzyloxycarbonyl-α-amino-α-methylglutarimide as a white solid: mp150.5-152.5° C.; ¹H NMR (CDCl₃) δ 8.21 (s, 1H), 7.34 (s, 5H), 5.59 (s,1H), 5.08 (s, 2H), 2.74-2.57 (m, 3H), 2.28-2.25 (m, 1H). 1.54 (s, 3H);¹³C NMR (CDCl₃) δ 174.06, 171.56, 154.68, 135.88, 128.06, 127.69,127.65, 66.15, 54.79, 29.14, 28.70, 21.98; HPLC : Waters Nova-Pak C18colunmn, 4 micron, 3.9×150 mm. 1 mL/min. 240 nm, 20/80 CH₃CN/0.1%H₃PO₄(aq), 7.56 min (100%); Anal. Calcd For C₁₄H₁₆N₂O₄; C, 60.86; H,5.84; N, 10.14. Found: C, 60.88; H. 5.72; N, 10.07.

[0074] In a similar fashion fromN-benzyloxycarbonyl-α-amino-α-ethylisoglutamine andN-benzyloxycarbonyl-α-amino-α-propylisoglutamine there is obtainedN-benzyloxycarbonyl-α-amino-α-ethylglutarimide andN-benzyloxycarbonyl-α-amino-α-propylglutarimide, respectively.

EXAMPLE 5 α-Amino-α-methylglutarimide hydrochloride

[0075] N-Benzyloxycarbonyl-α-amino-α-methylglutarimide (2.3 g, 8.3 mmol)was dissolved in ethanol (200 mL) with gentle heat and the resultingsolution allowed to cool to room temperature. To this solution was added4N hydrochloric acid (3 mL) followed by 10% Pd/C (0.4 g). The mixturewas hydrogenated in a Parr apparatus under 50 psi of hydrogen for 3hours. To the mixture was added water (50 mL) to dissolve the product.This mixture was filtered through a Celite pad which was washed withwater (50 mL). The filtrate was concentrated in vacuo to afford a solidresidue. The solid was slurried in ethanol (20 mL) for 30 min. Theslurry was filtered to afford 1.38 g (93%) ofα-amino-α-methylglutarimide hydrochloride as a white solid: ¹H NMR(DMSO-d₆) δ 11.25 (s, 1H), 8.92 (s, 3H), 2.84-2.51 (m, 2H), 2.35-2.09(m, 2H), 1.53 (s, 3H); HPLC, Waters Nova-Pak C₁₈ column, 4 micron, 1mL/min. 240 nm, 20/80 CH₃CN/0.1% H₃PO₄(aq), 1.03 min (94.6%).

[0076] In a similar fashion fromN-benzyloxycarbonyl-α-amino-α-ethylglutarimide andN-benzyloxycarbonyl-α-amino-α-propylglutarimide there is obtainedα-amino-α-ethylglutarimide hydrochloride and α-amino-α-propylglutarimidehydrochloride, respectively.

EXAMPLE 6 3-(3Nitrophthalimido)-3-methylpiperidine-2,6-dione

[0077] A stirred mixture of α-amino-α-methylglutarimide hydrochloride(1.2 g, 6.7 mmol), 3-nitrophthalic anhydride (1.3 g, 6.7 mmol), andsodium acetate (0.6 g, 7.4 mmol) in acetic acid (30 mL) was heated toreflux under nitrogen for 6 hours. The mixture then was cooled andconcentrated in vacuo. The resulting solid was slurried in water (30 mL)and methylene chloride (30 mL) for 30 min. The suspension was filtered,the solid was washed with methylene chloride, and dried in vacuo (60°C., <1 mm) to afford 1.44 g (68%) of3-(3-nitrophthalimido)-3-methylpiperidine-2,6-dione as a off-whitesolid: mp 265-266.5° C.; ¹H NMR (DMSO-d₆) δ 11.05 (s, 1H), 8.31 (dd,J=1.1 and 7.9 Hz, 1H), 8.16-8.03 (m, 2H), 2.67-2.49 (m, 3H), 2.08-2.02(m, 1H), 1.88 (s, 3H); ¹³C NMR (DMSO-d₆) δ 172.20, 171.71, 165.89,163.30, 144.19, 136.43, 133.04, 128.49, 126.77, 122.25, 59.22, 28.87,28.49, 21.04; HPLC, Water Nova-Pak/C₁₈ column. 4micron, 1 mL/min, 240nm, 20/80 CH₃CN/0.1% H₃PO₄(aq), 7.38 min(98%). Anal. Calcd ForC₁₄H₁₁N₃O₆: C, 53.00; H, 3.49; N, 13.24. Found: C, 52.77; H, 3.29; N,13.00.

[0078] In a similar fashion from α-amino-α-ethylglutarimidehydrochloride and α-amino-α-propylglutarimide hydrochloride there isobtained 3-(3-nitrophthalimido)-3-ethylpiperidine-2,6-dione and 3-(3-nitrophthalimido)-3-propylpiperidine-2,6-dione, respectively.

EXAMPLE 7 3-(3-Aminophthalimido)-3-methyl-piperidine-2,6-dione

[0079] 3-(3 -Nitrophthalimido)-3 -methylpiperidine-2,6-dione (0.5 g,1.57 mmol) was dissolved in acetone (250 mL) with gentle heat and thencooled to room temperature. To this solution was added 10% Pd/C (0.1 g)under nitrogen. The mixture was hydrogenated in a Parr apparatus at 50psi of hydrogen for 4 hours. The mixture then was filtered throughCelite and the pad washed with acetone (50 mL). The filtrate wasconcentrated in vacuo to yield a yellow solid. The solid was slurried inethyl acetate (10 mL) for 30 minutes. The slurry then was filtered anddried (60° C., <1 mm) to afford 0.37 g (82%) of3-(3-aminophthalimido)-3-methylpiperidine-2,6-dione as a yellow solid:mp 268-269° C.; ¹H NMR (DMSO-d₆) δ 10.98 (s, 1H), 7.44 (dd, J=7.1 and7.3 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.94 (d, J=6.9 Hz, 1H), 6.52 (s,2H), 2.71-2.47 (m, 3H). 2.08-1.99 (m, 1H), 1.87 (s, 3H); ¹³C NMR(DMSO-d₆) δ 172.48, 172.18, 169.51, 168.06, 146.55, 135.38, 131.80,121.51, 110.56, 108.30, 58.29, 29.25, 28.63, 21.00; HPLC, WaterNova-Pak/C₁₈ column, 4 micron, 1 mL/min, 240 nm, 20/80CH₃CN/0.1%H₃PO₄(aq), 5.62 min (99.18%). Anal. Calcd For C₁₄H₁₃N₃O₄ : C,58.53; H, 4.56; N, 14.63. Found: C, 58.60; H, 4.41; N, 14.36.

[0080] In a similar fashion from3-(3-nitrophthalimido)-3-ethylpiperidine-2,6-dione and3-(3-nitrophthalimido)-3-propylpiperidine-2,6-dione there is obtained3-(3-amino-phthalimido)-3-ethylpiperidine-2,6-dione and3-(3-aminophthalimido)-3-propyl-piperidine-2,6-dione, respectively.

EXAMPLE 8 Methyl 2-bromomethyl-3-nitrobenzoate

[0081] A stirred mixture of methyl 2-methyl-3-nitrobenzoate(17.6 g, 87.1mmol) and N-bromosuccinimide (18.9 g. 105 mmol) in carbon tetrachloride(243 mL) was heated under gentle reflux with a 100 W light bulb situated2 cm away shining on the reaction mixture overnight. After 18 hours, thereaction mixture was cooled to room temperature and filtered. Thefiltrate was washed with water (2×120 mL), brine(120 mL), and dried(MgSO₄). The solvent was removed in vacuo to give a yellow solid. Theproduct was purified by flash chromatography (hexane:ethyl acetate 8:2)to give 22 g (93%) of methyl 2-bromomethyl-3-nitrobenzoate as a yellowsolid: mp 69-72° C.; ¹H NMR (CDCl₃) δ 8.13-8.09 (dd, J=1.36 and 7.86 Hz,1H), 7.98-7.93 (dd, J=1.32 and 8.13 Hz, 1H), 7.57-7.51 (t, J=7.97Hz,1H), 5.16 (s, 2H), 4.0 (s, 3H); ¹³C NMR (CDCl₃) δ 65.84, 150.56, 134.68,132.64, 132.36, 129.09, 53.05, 22.70; HPLC Waters Nova-Pak C₁₈ column,4micron, 1 mL/min, 240 nm, 40/60 CH₃CN/0.1%H₃PO₄(aq), 8.2 min 99%. Anal.Calcd for C₉H₈NO₄Br: C, 39.44; H, 2.94; N, 5.11, Br, 29.15. Found: C,39.51; H, 2.79; N, 5.02; Br, 29.32.

EXAMPLE 9 3-(1-Oxo-4-nitroisoindolin-1-yl)-3-methylpiperidine-2,6-dione

[0082] To a stirred mixture of α-amino-α-methylglutarimide hydrochloride(2.5g, 14.0 mmol) and methyl 2-bromomethyl-3-nitrobenzoate(3.87g, 14.0mmol in dimethylformamide (40 mL) was added triethylamine (3.14 g, 30.8mmol). The resulting mixture was heated to reflux under nitrogen for 6hours. The mixture was cooled and then concentrated in vacuo. Theresulting solid was slurried in water (50 mL) and CH₂Cl₂ for 30 min. Theslurry was filtered, the solid washed with methylene chloride, and driedin vacuo (60° C., <1 mm) to afford 2.68 g (63%) of3-(1-oxo-4-nitroisoindolin-1-yl)-3-methylpiperidine-2,6-dione as aoff-white solid: mp 233-235° C.; ¹H NMR (DMSO-d₆) δ 10.95 (s, 1H),8.49-8.46 (d, J=8.15 Hz, 1H), 8.13-8.09 (d, J=7.43 Hz, 1H), 7.86-7.79(t, J=7.83 Hz, 1H), 5.22-5.0 (dd, J=19.35 and 34.6 Hz, 2H), 2.77-2.49(m, 3H), 2.0-1.94 ( m, 1H), 1.74 (S, 3H); ¹³C NMR (DMSO-d₆) δ 173.07,172.27, 164.95, 143.15, 137.36, 135.19, 130.11, 129.32, 126.93, 57.57,48.69, 28.9, 27.66, 20.6; HPLC. Waters Nova-Pak C₁₈ column, 4micron, 1mL/min, 240 nm, 20/80 CH₃CN/0.1%H₃PO₄(aq), 4.54 min 99.6%. Anal. Calcdfor C₁₄H₁₃N₃O₅: C, 55.45; H, 4.32; N, 13.86. Found: C, 52.16; H, 4.59;N, 12.47.

[0083] By substituting equivalent amounts of α-amino-α-ethylglutarimidehydrochloride and α-amino-α-propylglutarimide hydrochloride forα-amino-α-methylglutarimide hydrochloride, there is obtainedrespectively3-(1-oxo-4-nitroisoindolin-1-yl)-3-ethylpiperidine-2,6-dione and3-(1-oxo-4-nitroisoindolin-1-yl)-3-propylpiperidine-2,6-dione.

EXAMPLE 10 3-(1-Oxo-4-aminoisoindolin-1-yl)-3-methylpiperidine-2,6-dione

[0084] 3-(1-Oxo-4-nitroisoindolin-1-yl)-3-methylpiperidine-2,6-dione(1.0 g, 3.3 mmol) was dissolved in methanol (500 mL) with gentle heatand allowed to cool to room temperature. To this solution was added 10%Pd/C (0.3 g) under nitrogen. The mixture was hydrogenated in a Parrapparatus at 50 psi of hydrogen for 4 hours. The mixture was filteredthrough celite and the celite washed with methanol (50 mL). The filtratewas concentrated in vacuo to an off white solid. The solid was slurriedin methylene chloride (20 mL) for 30 min. The slurry was then filteredand the solid dried (60° C., <1 mm) to afford 0.54 g (60%) of3-(1-oxo-4-aminoisoindolin-1-yl)-3-methylpiperidine-2,6-dione as a whitesolid: mp 268-270° C.; ¹H NMR (DMSO-d₆) δ 10.85 (s, 1H), 7.19-7.13 (t,J=7.63 Hz, 1H), 6.83-6.76 (m, 2H), 5.44 (s, 2H), 4.41(s, 2H), 2.71-2.49(m, 3H), 1.9-1.8 (m, 1H), 1.67 (s, 3H); ¹³C NMR (DMSO-d₆) δ 173.7,172.49, 168.0, 143.5, 132.88, 128.78, 125.62, 116.12, 109.92, 56.98,46.22, 29.04, 27.77, 20.82; HPLC, Waters Nova-Pak/C18 column, 4 micron,1 mL/min. 240 nm, 20/80 CH₃CN/0.1%H₃PO₄(aq), 1.5 min (99.6%); Anal.Calcd for C₁₄H₁₅N₃O₃: C, 61.53; H, 5.53; N, 15.38. Found: C, 58.99; H,5.48; N, 14.29.

[0085] From 3-(1-oxo-4-nitroisoindolin-1-yl)-3-ethylpiperidine-2,6-dioneand 3-(1-oxo-4-nitroisoindolin-1-yl)-3-propylpiperidine-2.6-dione thereis similarly obtained3-(1-oxo-4-aminoisoindolin-1-yl)-3-ethylpiperidine-2.6-dione and3-(1-oxo-4-aminoisoindolin-1-yl)-3-propylpiperidine-2,6-dione,respectively.

EXAMPLE 11

[0086] Tablets, each containing 50 mg of1-oxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4,5,6,7-tetrafluoroisoindoline,can be prepared in the following manner: Constituents (for 1000 tablets)1-oxo-2-(2,6-dioxo-3-methyl 50.0 g piperidin-3-yl)-4,5,6,7-tetrafluoroisoindoline lactose 50.7 g wheat starch  7.5 g polyethyleneglycol 6000  5.0 g talc  5.0 g magnesium stearate  1.8 g demineralizedwater q.s.

[0087] The solid ingredients are first forced through a sieve of 0.6 mmmesh width. The active ingredient, lactose, talc, magnesium stearate andhalf of the starch then are mixed. The other half of the starch issuspended in 40 mL of water and this suspension is added to a boilingsolution of the polyethylene glycol in 100 mL of water. The resultingpaste is added to the pulverulent substances and the mixture isgranulated, if necessary with the addition of water. The granulate isdried overnight at 35° C., forced through a sieve of 1.2 mm mesh widthand compressed to form tablets of approximately 6 mm diameter which areconcave on both sides.

EXAMPLE 12

[0088] Tablets, each containing 100 mg of1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline, can be prepared inthe following manner: Constituents (for 1000 tablets)1-oxo-2-(2,6-dioxo- 100.0 g piperidin-3-yl)-4-amino isoindoline lactose100.0 g wheat starch  47.0 g magnesium stearate  3.0 g

[0089] All the solid ingredients are first forced through a sieve of 0.6mm mesh width. The active ingredient, lactose, magnesium stearate andhalf of the starch then are mixed. The other half of the starch issuspended in 40 mL of water and this suspension is added to 100 mL ofboiling water. The resulting paste is added to the pulverulentsubstances and the mixture is granulated, if necessary with the additionof water. The granulate is dried overnight at 35° C., forced through asieve of 1.2 mm mesh width and compressed to form tablets ofapproximately 6 mm diameter which are concave on both sides.

EXAMPLE 13

[0090] Tablets for chewing, each containing 75 mg of 2-(2,6-dioxo-3-methylpiperidin-3-yl)-4-aminophthalimide, can be prepared in thefollowing manner: Composition (for 1000 tablets)2-(2,6-dioxo-3-methylpiperidin-  75.0 g 3-yl)-4-aminophthalimidemannitol 230.0 g lactose 150.0 g talc  21.0 g glycine  12.5 g stearicacid  10.0 g saccharin  1.5 g 5% gelatin solution q.s.

[0091] All the solid ingredients are first forced through a sieve of0.25 mm mesh width. The mannitol and the lactose are mixed, granulatedwith the addition of gelatin solution, forced through a sieve of 2 mmmesh width, dried at 50° C. and again forced through a sieve of 1.7 mmmesh width. 2-(2,6-Dioxo-3-methylpiperidin-3-yl)-4-aminophthalimide, theglycine and the saccharin are carefully mixed, the mannitol, the lactosegranulate, the stearic acid and the talc are added and the whole ismixed thoroughly and compressed to form tablets of approximately 10 mmdiameter which are concave on both sides and have a breaking groove onthe upper side.

EXAMPLE 14

[0092] Tablets, each containing 10 mg of2-(2,6-dioxoethylpiperidin-3-yl)-4-aminophthalimide, can be prepared inthe following manner: Composition (for 1000 tablets)2-(2,6-dioxoethylpiperidin-3-yl)-  10.0 g 4-aminophthalimide lactose328.5 g corn starch  17.5 g polyethylene glycol 6000  5.0 g talc  25.0 gmagnesium stearate  4.0 g demineralized water q.s.

[0093] The solid ingredients are first forced through a sieve of 0.6 mmmesh width. Then the active imide ingredient, lactose, talc, magnesiumstearate and half of the starch are intimately mixed. The other half ofthe starch is suspended in 65 mL of water and this suspension is addedto a boiling solution of the polyethylene glycol in 260 mL of water. Theresulting paste is added to the pulverulent substances, and the whole ismixed and granulated, if necessary with the addition of water. Thegranulate is dried overnight at 35° C., forced through a sieve of 1.2 mmmesh width and compressed to form tablets of approximately 10 mmdiameter which are concave on both sides and have a breaking notch onthe upper side.

EXAMPLE 15

[0094] Gelatin dry-filled capsules, each containing 100 mg of1-oxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4,5,6,7-tetrafluoroisoindoline,can be prepared in the following manner: Composition (for 1000 capsules)1-oxo-2-(2,6-dioxo-3- 100.0 g methylpiperidin-3-yl)-4,5,6,7-tetrafluoroisoindoline microcrystalline cellulose  30.0 g sodium laurylsulfate  2.0 g magnesium stearate  8.0 g

[0095] The sodium lauryl sulfate is sieved into the1-oxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4,5,6,7-tetrafluoroisoindolinethrough a sieve of 0.2 mm mesh width and the two components areintimately mixed for 10 minutes. The microcrystalline cellulose is thenadded through a sieve of 0.9 mm mesh width and the whole is againintimately mixed for 10 minutes. Finally, the magnesium stearate isadded through a sieve of 0.8 mm width and, after mixing for a further 3minutes the mixture is introduced in portions of 140 mg each into size 0(elongated) gelatin dry-fill capsules.

EXAMPLE 16

[0096] A 0.2% injection or infusion solution can be prepared, forexample, in the following manner: 1-oxo-2-(2,6-dioxo-3-methyl   5.0 gpiperidin-3-yl)-4,5,6,7-tetrafluoro isoindoline sodium chloride  22.5 gphosphate buffer pH 7.4  300.0 g demineralized water to 2500.0 mL

[0097]1-Oxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4,5,6,7-tetrafluoroisoindolineis dissolved in 1000 mL of water and filtered through a microfilter. Thebuffer solution is added and the whole is made up to 2500 mL with water.To prepare dosage unit forms, portions of 1.0 or 2.5 mL each areintroduced into glass ampoules (each containing respectively 2.0 or 5.0mg of imide).

What is claimed is:
 1. A 2,6-dioxopiperidine selected from the groupconsisting of (α) a compound of the formula:

in which: one of X and Y is C═O and the other of X and Y is C═O or CH₂;(i) each of R¹, R², R³, and R⁴, independently of the others, is halo,alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii)one of R¹, R², R³, and R⁴ is —NHR and the remaining of R¹, R², R³, andR⁴ are hydrogen; R⁵ is hydrogen, alkyl of 1 to 8 carbon atoms, orCO—R⁷—CH(R¹⁰)NR⁸R⁹; R⁶ is hydrogen, alkyl of 1 to 8 carbon atoms, benzo,chloro, or fluoro; R⁷ is m-phenylene or p-phenylene or —(C_(n)H_(2n))—in which n has a value of 0 to 4; each of R⁸ and R⁹ taken independentlyof the other is hydrogen or alkyl of 1 to 8 carbon atoms, or R⁸ and R⁹taken together are tetramethylene, pentamethylene, hexamethylene, or—CH₂CH₂XCH₂CH₂— in which X is —O—, —S— or —NH—; R¹⁰ is hydrogen, alkylof 1 to 8 carbon atoms, or phenyl; and (b) the acid addition salts ofsaid compounds which contain a nitrogen atom capable of beingprotonated.
 2. A compound according to claim 1 in which each of R¹, R²,R³, and R⁴, independently of the others, is halo, alkyl of 1 to 4 carbonatoms, or alkoxy of 1 to 4 carbon atoms; R⁶ is hydrogen, methyl, ethyl,or propyl; R⁷ is m-phenylene or p-phenylene; each of R⁸ and R⁹ takenindependently of the other is hydrogen or methyl; and R¹⁰ is hydrogen.3. A compound according to claim 1 in which each of R¹, R², R³, and R⁴,independently of the others, is halo, alkyl of 1 to 4 carbon atoms, oralkoxy of 1 to 4 carbon atoms; R⁶ is hydrogen, methyl, ethyl, or propyl;R⁷ is —(C_(n)H_(2n))— in which n has a value of 0 to 4; each of R⁸ andR⁹ taken independently of the other is hydrogen or methyl; and R¹⁰ ishydrogen.
 4. A compound according to claim 1 in which one of R¹, R², R³,and R⁴ is —NH₂ and the remaining of R¹, R², R³, and R⁴ are hydrogen; R⁶is hydrogen, methyl, ethyl, or propyl; R⁷ is m-phenylene or p-phenylene;each of R⁸ and R⁹ taken independently of the other is hydrogen ormethyl; and R¹⁰ is hydrogen.
 5. A compound according to claim 1 in whichone of R¹, R², R³, and R⁴ is —NH₂ and the remaining of R¹, R², R³, andR⁴ are hydrogen; R⁶ is hydrogen, methyl, ethyl, or propyl; R⁷ is or—(C_(n)H_(2n))— in which n has a value of 0 to 4; each of R⁸ and R⁹taken independently of the other is hydrogen or methyl; and R¹⁰ ishydrogen.
 6. A 2,6-dioxopiperidine selected from the group consisting of(α) a compound of the formula:

in which: one of X and Y is C═O and the other of X and Y is C═O or CH₂;(i) each of R¹, R², R³, and R⁴, independently of the others, is halo,alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii)one of R¹, R², R³, and R⁴ is —NHR and the remaining of R¹, R², R³, andR⁴ are hydrogen; R⁵ is hydrogen, alkyl of 1 to 8 carbon atoms, orCO—R⁷—CH(R¹⁰)NR⁸R⁹; R⁶ is alkyl of 1 to 8 carbon atoms, benzo, chloro,or fluoro; R⁷ is m-phenylene or p-phenylene or —(C_(n)H_(2n))— in whichn has a value of 0 to 4; each of R⁸ and R⁹ taken independently of theother is hydrogen or alkyl of 1 to 8 carbon atoms, or R⁸ and R⁹ takentogether are tetramethylene, pentamethylene, hexamethylene, or—CH₂CH₂XCH₂CH₂— in which X is —O—, —S— or —NH—; R¹⁰ is hydrogen, alkylof 1 to 8 carbon atoms, or phenyl; and (b) the acid addition salts ofsaid compounds which contain a nitrogen atom capable of beingprotonated.
 7. A compound according to claim 6 in which each of R¹, R²,R³, and R⁴, independently of the others, is halo, alkyl of 1 to 4 carbonatoms, or alkoxy of 1 to 4 carbon atoms and R⁶ is methyl, ethyl, orpropyl.
 8. A compound according to claim 6 in which one of R¹, R², R³,and R⁴ is —NH₂ and the remaining of R¹, R², R³, and R⁴ are hydrogen andR⁶ is methyl, ethyl, or propyl.
 9. The method of reducing undesirablelevels of TNFα in a mammal which comprises administering thereto aneffective amount of a compound according to claim
 1. 10. The method ofreducing undesirable levels of TNFα in a mammal which comprisesadministering thereto an effective amount of a compound according toclaim
 6. 11. A pharmaceutical composition comprising a quantity of acompound according to claim 1 sufficient upon administration in a singleor multiple dose regimen to reduce levels of TNFα in a mammal incombination with a carrier.
 12. A pharmaceutical composition comprisinga quantity of a compound according to claim 6 sufficient uponadministration in a single or multiple dose regimen to reduce levels ofTNFα in a mammal in combination with a carrier.